Quaternary ammonium salts of organic carboxylic acid esters of 1-dialkyl-aminoethanols-2



Aug. 3, 1965 K. ZEILE ETAL 3,198,825 ACID QUATERNARY AMMONIUM SALTS OF ORGANIC CARBOXYLIC ESTERS OF l-DIALKYLAMINO-ETHANOLS-Z 3 Sheets-Sheet 1 Filed Nov. 10, 1960 SPASMOLYTIC ACTIVITY SIDE EFFECTS KM! IEVE TORS W? HM will ATTORNEYS 3, 1965 K. ZEILE ETAL 3,198,825

M SALTS OF ORGANIC CARBOXYLIC ACID QUATERNARY ANHONIU ESTERS OF lDIALKYLAMINO-ETHANOLS2 3 Sheets-Sheet 2 Filed Nov. 10. 1960 g- 3, 1955 K. ZEILE ETAL 3,198,825

QUATERNARY AMMONIUM SALTS OF ORGANIC CARBQXYLIC ACID 3 Sheets-Sheet 3 ESTERS OF 1-DIALKYLAMINO-ETHANOLS-2 Filed Nov. 10, 1960 SI E EFFECTS OOOI O-OOOI United States Patent 3,198,825 QUATERNARY AMMONIUM SALTS 0F ORGANKQ CARBQXYLHI AtIID ESTERS 0h l-DIALKYL- GETHANGLS-Z Karl Zeiie, Franz Adiclres, and Helmut Wick, Ingelheirn (Rhine), Germany, assignors, by mesne assignments, to Boehringer Ingelheim G.m.b.H., 1 Ingelheirn (Rhine), Germany, a corporation of Germany Filed Nov. 10, 1960, Ser. No. 68,517 Claims priority, application Germany, Mar. 19, 1955, B 34,944 4 Claims. (Cl. 269-473) This is a continuation-in-part of copending application Serial No. 585,599, filed March 19, 1956, now abandoned.

The present invention relates to quaternary ammonium salts of organic carboxylic acid esters of l-dialkylaminoethanol-2.

More particularly, the present invention relates to nontoxic, pharmacologically acceptable quaternary ammonium salts having the structural formula wherein Y is organic acyl selected from the group consisting of benziloyl, hexahydrobenziloyl, diphenyl-acetyl and cyclohexylphenyl-acetyl,

R and R are lower alkyl,

R is alkyl with 6 to 11 carbon atoms, inclusive, and

X is a pharmacologically non-toxic anion, e.g. chloride, bromide, iodide, sulfate, methane-sulfonate, nitrate or salicylate.

It is known that among organic carboxylic acid esters of lower amino-alkanols comprising a tertiary amino group there are very effective spa-smolytics. However, the spasmolytic effect of all of these known esters is accompanied by substantial undesirable side effects which either stand in the way of the practical pharmaceutical application of such esters or restrict their use in combatting myotropic and neurotropic spasms to very low doses. Among others, these undesirable side effects include reduction of saliva secretion, whereby very unpleasant thirst and dryuess-of-the-mouth sensations are created, mydriasis, considerable acceleration of the pulse rate and a very undesirable reduction of the blood pressure.

It is further known that the spasmolytic activity of such esters can be further increased by introducing a quaternary radical into the aminoalkanol moiety, that is by quaternizing the amino nitrogen with a suitable quaternizing agent, particularly with a lower alkyl halide or a lower alkyl sulfate, and preferably with methyl halides and methyl sulfate. However, the increase in the spasmolytic activity brought about by such quaternization is also accompanied by a substantially proportionate increase in the intensity of the undesirable side elfects.

The reason for this behavior was found when the carbon chain length of the quaternary alkyl group was systematically increased and the intensity of the spasmolytic activity and the side efiects of the resulting compounds were investigated in each case. It was found that after an initial substantially proportionate increase of both spas molytic activity and side eifects upon introduction of a quaternary methyl group, the spasmolytic activity and the side effects decrease sharply and substantially proportionately upon introduction of a quaternary alkyl radical with more than one carbon atom, so' that such higher quaternary ammonium salts become completely unsuitable for practical use as spasmolytics. This decrease in ice activity and side effects was found to continue with an increase of the number of carbon atoms in the quaternary alkyl group up to and including'five carbon atoms. At this point the prior art workers apparently assumed that a further lengthening of the carbon chain of the quaternary alkyl radical would only result in further proporti-onal depression of the spasmolytic activity and the side effects.

We have now surprisingly discovered that upon introduction of quaternary alkyl groups with still longer carbon chains, particularly 6 to 11 carbon atoms, the spasmolytic activity of the quaternary ammonium salts of (Ldialkylamino-ethanol-2)-organic acid carboxylates again increase, in some cases to an intensity even greater than that of the corresponding methyl quaternary salt, while the intensities of the undesirable side efiects substantially remain as low as or even drop below the negligible values to which they decrease upon lengthening the carbon chain of the quaternary alkyl group above one carbon atom up to five carbon atoms. In other Words, we have discovered that, contrary to reasonable expectation, quaternary ammonium salts embraced by Formula '1 above exhibit the highly desirable combination of highly effective spasmo lytic activity coupled with a very low and even practically negligible intensity of the undesirable side efiects enumerated above. a

The novel quaternary ammonium salts according to the present invention may be prepared by any one of a number of known methods. Particularly advantageous are the following:

A. Quaterniz'ation of a (1dialkylamino-ethanol-2-)organic acid carboxylate with an alkylhalide or an alkyl sulfate in accordance with the following reaction equations:

R1 Y0GHg'CH N 33X 1 R YO-OH CH -N\ R X I Ra wherein Y, R R R and X have the meanings defined above in' connection with Formula I.

B. Reaction of a ,B-halo-ethanol organic acid carboxylate with a trialkylamine in accordance with the following reaction equation:

wherein Y, R R and R have the meanings defined above and Hal is a halogen, particularly chlorine, bromine or iodine. Of course, this particular method yields only those quaternary ammonium salts of the Formula I wherein X is halogen.

The following examples will further illustrate various methods of preparing compounds embraced by Formula I, but it will be understood that the present invention is not limited to the particular compounds obtained in these illustrative examples.

EXAMPLE I.-BENZILIC ACID ESTER OF 1 (DI- METHYL N OCTYL AMMONIUM BROMIDE)- ETHANOL-2 gm. (about /2 mol) of the benzilic acid ester of l-dimethylamino-ethanol-2 were dissolved in 750 cc. of acetonitrile and 200 gm. (about 1 mol) of n-octyl bromide were added to the solution. The resulting reaction mixture was maintained at a temperature of 60 C. for about 10 days. Thereafter the acetonitrile solvent and the excess n-octyl bromide were distilled off in vacuo' on a water bath. The distillation residue was recrystallized from acetone, yielding 216 gm. (87.5% of theory) of the benzilic acid ester of 1-(dimethyl-n-octyl-ammonium bromide)-ethanol-2. In order to remove all traces of remaining n-octyl bromide the recrystallized product was once again recrystallized from acetone. The pure product had a melting point of 115 C., and analysis showed that it had the structural formula The corresponding n-octyl ammonium chloride was obtained substituting n-octyl chloride for n-octyl bromide in the above procedure. It had a melting point of 133 C.

The corresponding n-octyl ammonium iodide was obtained substituting n-octyl iodide for n-octyl bromide in the above procedure. M.P. 110 to 112 C.

The corresponding n-octyl ammonium sulfate was obtained as follows:

4.9 gm. (0.01 mol) of the quaternary ammonium bromide were shaken for two hours in 300 cc. water with 15.6 gm. (0.005 mol) silver-sulfate. Thereafter, ethanol was added and the mixture was allowed to stand over night. The silver-bromide precipitated thereby was filtered off and the filtrate was evaporated to dryness in vacuo at a temperature of 100 C. The evaporation residue was recrystallized from acetonitrile. 4.2 gm. (91% of theory) of benzilic acid ester of l-(dimethyl-n-octylammonium sulfate)-ethanol-2 with a melting point of 128 C. were obtained. 7

The corresponding n-octyl-ammonium-methane sulfonate was obtained by an analogous procedure but using about 0.01 mol silver-methane sulfonate in place of 0.005 mol silver-sulfate and recrystallizing the reaction product from acetic acid ester instead of acetonitrile. M.P. 84 C.

The corresponding n-octyl-ammonium nitrate was obtained by an analogous procedure but using about 0.01 mol silver-nitrate in place of 0.005 mol silver-sulfate and recrystallizing the reaction product from benzene instead of acetonitrile. M.P. 68 to 73 C.

The corresopnding n-octyl-ammonium tartrate was obtained as follows:

0.01 mol of the quaternary ammonium bromide were shaken for two hours in 300 cc. water with 0.01 mol of sodium tartrate. Thereafter, the mixture was extracted with chloroform and the organic layer was evaporated to dryness in vacuo. The remaining residue was recrystallized from acetic acid ester. M.P. 117 to 120 C.

The corresponding n-octyl-ammonium salicylate was obtained by an analogous procedure but using about 0.01 mol sodium salicylate instead of sodium tartrate. M.P. 118 to 120 C.

EXAMPLE II.BENZILIC ACID ESTER OF l-(DI- ETHYL N OCTYL AMMONIUM BROMIDE)- ETHANOL-2 33 gm. (about 0.1 mol) of the benzilic acid ester of l-diethylamino-ethanol-Z were dissolved in 50 cc. of acetonitrile, and 38.6 gm.(about 0.2 mol) of n-octyl bromide were added to the solution. The resulting reaction mixture was then maintained at a temperature of 60 C. for 9 days and at the end of this period the acetonitrile was evaporated in vacuo. The residue was dissolved in ethanol, reprecipitated therefrom with ether and recrystallized from acetone. 32 gm. (62% of theory) of a compound having the structural formula and a melting point of 144 to 145 C. were obtained.

41. EXAMPLE III.DIPHEl lYL-ACETIC ACID ESTER OF -1-(DIETHYL N GCTYL-AMMONIUM BRO- MIDE -ETHANOL-2 and a melting point of 106 to 107 C. were obtained.

EXAMPLE IV .BENZILIC ACID ESTER OF 1-(DI- METHYL N HEXYL AMMONIUM BROMIDE)- ETHANOL-2 By following the procedure described in Example I, but using an equivalent amount of n-hexyl bromide in place of n-octyl bromide, a compound having the structural formula and a melting point of 114 to 116 C. was obtained.

EXAMPLE V.BENZILIC ACID ESTER OF l-(DI- METHYL N-HEPTYL-AMMONIUM-BROMIDE)- ETHANOL-2 By following the procedure described in Example I, but using an equivalent amount of n-heptyl bromide in place of n-octyl bromide and i'ecrystallizing the reaction product from ethyl acetate, a compound having the structural formula and a melting point of 121 to 122 C. was obtained.

EXAMPLE VI.BENZILIC ACID ESTER OF l-(DI- METHYL N NONYL-AMMONIUM BROMIDE)- ETHANOL-2 By following the procedure described in Example I, but using an equivalent amount of n-nonyl bromide in place of n-octyl bromide and recrystallizing the reaction product from ethyl acetate, a compound having the structural formula and a melting point of 57 to 58 C. was obtained.

EXAMPLE VII.BENZILIC ACID ESTER OF l-(DI- METHYL N DECYL-AMMONIUM BROMIDE)- ETHANOL-2 By following the procedure described in Example I, but using an equivalent amount of n-decyl bromide in place of n-octyl bromide and recrystallizing the reaction product from a mixture of ethanol and ether, a compound having the structural formula and a melting point of 120 to 124 C. was obtained.

EXAMPLE VHLBENZILIC ACID ESTER OF l-(DI- METHYL N UNDECYL AMMONIUM BRO MIDE) ETHANOL-2 By following the procedure described in Example I, but using an equivalent amount of n-undecyl bromide in place of n-octyl bromide and recrystallizing the reaction product from isopropanol, a compound having the structural formula and a melting point of 123 to 124 C. was obtained.

EXAMPLE IX.-BENZILIC ACID ESTER OF l-(DI- ETHYL N HEXYL AMMONIUM BROMIDE)- ETHANOL-2 By following the procedure described in Example 11, but using an equivalent amount of n-hexyl bromide in place of n-octyl bromide, a compound having the structural formula and a melting point of 134 to 135 C.

EXAMPLE X.--BENZILIC ACID ESTER OF l-(DI- ETHYL N HEPTYL-AMMONIUM BROMIDE)- ETHANOL-Z By following the procedure described in Example 11, but using an equivalent amount of n-heptyl bromide in place of n-octyl bromide and recrystallizing the reaction product from isopropanol, a compound having the structural formula o -ooo-om-oHr-i mm -Br- {3 011 onmons and a melting point of 157 to 158 C. was obtained.

EXAMPLE XI.--BENZILIC ACID ESTER OF l-(DI- ETHYL N NONYL AMMONIUM BROMIDE) ETHANOL-2 By following the procedure described in Example II,

but using an equivalent amount of n-nonyl bromide in place of n-octyl bromide, a compound having the structural formula and a melting point of 144 C. was obtained.

EXAMPLE X]I.BENZILIC ACID ESTER OF l-(DI- ETHYL-N-DECYL-AMMONIUM BROMIDE)-ETH- ANOL-2 By following the procedure described in Example II, but using an equivalent amount of n-decyl bromide in place of n-octyl bromide, a compound having the structural formula and a melting point of 145 to 146 C. was obtained.

EXAMPLE XIIL-BENZILIC ACID ESTER OF l-(DI- ISOPROPYL-N-OCTYL-AMMONIUM BROMIDE) ETHANOL-2 By following a procedure analogous to that described in Example I, but using an equivalent amount of the benzilic acid ester of 1-diisopropyla.mino-ethanol-Z and recrystallizing the reaction product from ethyl acetate, a compound having the structural formula Q o-ooo-on onrf r-onwnm 'Br- Q/OH (CH2)7CH3 and a melting point of 150 to 152 C. was .obtained.

EXAMPLE XIV.PHENYL-CYCLOHEXYL-GLY COLIC ACID ESTER OF l-(DIMETHYL-N-HEP- TYL-AMMONIUM iBROMID'EMETHANOL-Z By following the procedure described in Example I but using equivalent amounts of the phenyl-cyclohexylglycolic acid ester of l-dimethyl-amino-ethanol-Z and n- 'heptyl bromide in placeof the benzilic acid ester of 1- dimethylamino-ethanol-2 and n-octyl bromide and recrystallizing the reaction product from ethyl acetate, a compound having the structural formula and a melting point of 103 to 106 C. was obtained.

EXAMPLE XV.--PHENYL-CYCLOHEXYL-GLYCOL- IC ACID ESTER OF l-(DIMETHYL-N-OCTYL-AM- MONIUM BROMIDE) ETHANOL-2 By following the procedure described in Example I, but using an equivalent amount of the phenyl-cyclohexylglycolic acid ester of 1-dimethylamino-ethanol-2 in place of the benzilic acid ester of 1-dimethylamino-ethanol-2, a compound having the structural formula and a melting point of 104 to 105 C. was obtained.

and a melting point of 113 to 115 C. was obtained.

'2 EXAMPLE XVII.--PI-IENYL-CYCLOHEXYL-GLY- COLIC ACID ESTER OF l-(DIETHYL- -HEXYL- AMMONIUM BROMIDE)-ETHANOL-2 and a melting point of 98 to 102 C. was obtained.

EXAMPLE XVIII.PHENYL-CYCLOHEXYL-GLY- COLIC ACID ESTER OF I-(DIETHYLN-HEPTYL AMMONIUM BROMIDE)-ETHANOL-2 By following the procedure described in Example II, but starting from phenyl-cyclohexyl-glycolic acid ester of l-diethylamino-ethanol-Z and n-heptyl bromide, and recrystallizing the reaction product from ethyl acetate, a compound having the structural formula and a melting point of 134 to 136 C. was obtained.

EXAMPLE XIX.PHENYL CYCLOHEXYL GLY- COLIC ACID ESTER OF l-(DIETHYL-N-OCTYL- AMMONIUM BROMIDE)-ETHANOL-2 By following the procedure described in Example II, but starting from phenyl-cyclohexyl-glycolic acid ester of l-diethylamino-ethanol-Z and recrystallizing the reaction product from ethyl acetate, a compound having the structural formula and a melting point of 134 to 135 C. was obtained.

EXAMPLE XX.PHENYL CYCLOHEXYL GLY- COLIC ACID ESTER OF l-(DIETHYL-N-NONYL- AMMONIUM BROMIDE)-ETHANOL-2 and a melting point of 113 to 115 C. was obtained.

EXAMPLE XXI.DIPHENYL-ACETIC ACID ESTER OF 1 (DIMETHY L N OCTYL AMMONIUM BROMIDE) ETHANOL-2 By following the procedure described in Example III, but starting from diphenyl-acetic acid ester of l-dimethylamino-ethanol-2 and recrystallizing the reaction product from acetone, a compound having the structural formula and a melting point of 73C. was obtained.

EXAMPLE XXII.DIPHENYL ACETIC ACID ESTER OF I- (DIETHYL-N-HEXYL-AMMONIUM BROMIDE) -ETHANOL-2 By following the procedure described in Example III, but using an equivalent amount of n-hexyl bromide in place of n-octyl bromide, a compound having the structural formula and a melting point of 106 C. was obtained.

EXAMPLE XXIII.-DIPHENYL ACETIC ACID ESTER OF 1-(DIETHYL-N-DECYL-AMMONIUM BROMIDE) -ETHANOL-2 By following the procedure described in Example III, but using an equivalent amount of n-decyl bromide in place of n-octyl bromide, a compound having the structural formula and a melting point of 107 C. was obtained.

EXAMPLE XXIV.--PHENYL-CYCLOHEXYL-ACE TIC ACID ESTER OF l-(DIMETHYL-N-OCTYL AMMONIUM BROMIDE)-ETHANOL-2 By following the procedure described in Example III but starting with an equivalent amount of phcnyl-cyclo hexyl-acetic acid ester of l-dimethylarnino-ethanol-2, a compound having the structural formula and a melting point of 113 to 115 C. was obtained.

As indicated above, the quaternary ammonium salts embraced by Formula I exhibit the unexpected combination of high spasmolytic activity coupled with extremely low, virtually negligible side effects. The unexpected divergence, as opposed to expected parallelism, of spasmolytic activity and side effects can best be visualized and illustrated with the aid of the results of comparative tests which are shown in the tables below and graphically represented in the attached drawings.

The results listed in Tables I, II, III and IV below were obtained by varying the length of the carbon chain of the quaternary alkyl radical R in the compounds and determining the spasmolytic activity as well as the intensity of the side effects, as represented by the mydriatic activity, for each quaternary alkyl variation. The spasmolytic activity was measured on isolated guinea pig intestines wherein spasms had been artificially induced with acetyl-choline and in some instances also on isolated intestines which had been made spastic with barium chloride, using the experimental method of R. Magnus [Pflugers Archiv., vol. 102, page 124 (1904)]. The values for each compound in question are shown in the tables below in terms of its relative activity in relation to the corresponding activities of atropine or papaverine, respectively.

Relative Spasmolytic Activity Relative Value of Side Efiects Dilatation oi pu- R Isolated intestine Isolated intestine pils (mydriasis) against acetylagainst barium in white mice, choline; atropine chloride; papavsubcutaneous =1 erine=1 injection;

atropine 1 n-Heptyl lo n-Octyl Vs-Mo 5 n-Nonyl About l loo Table III Relative Spasmolytie Activity Isolated intestine against acetyl- Isolated intestine against barium Relative Value of Side Efiects Dilatation of pupils (mydriasis) in white mice,

choline; atropine chloride: papavsub cutaneous =1 erine=1 injection;

atropine 1 i r20 l ,too be A 000 About Mrs-lo The present invention is further illustrated by the attached drawings of which:

FIG. 1 represents a graphic plot on log-paper of the effect of varying the length of the carbon chain of the .quaternary alkyl radical in the phenyl-cyclohexyl glycolic acid ester of a l-(dimethyl-alkyl-ammonium bromide)- ethanol-2, with respect to the spasrnclytic activity and the side efl ects. The graphic representation also includes the corresponding values of the unquaternized tertiary aminoethanol ester. The abscissa of this graph represents the relative intensity of spasmolytic and mydriatic effects produced by the various compounds in relation to the corresponding intensities produced by atropine. The ordinate of the graph represents the variation of the carbon chain lentgh in the quaternary alkyl radical R. The solid line curve represents the fluctuations of the relative spasmolyt-ic activity and the broken line curve represents the fluctuations of the intensity of mydriasis.

FIG. 2 represents an analogous plot for the phenylcyclohexyl-glycolic acid ester of a l-(diethyl-ialkyl-ammonium bromide)-ethanol-2 and the corresponding diethylamino-ethano'l ester.

FIG. 3 represents an analogous plot for the diphenylacetic acid ester of a l-(diethylalkyl ammonium bromide)-ethanol-2 and the corresponding diethy-laminoethanol ester. The symbol f? used in designating the very low points of the side eifects curve means less than, that is substantially lower than the lowest value plottable on the graph.

A visual examination of Tables I, II, III and IV and FIGS. 1, 2 and 3 of the drawings will readily illustrate to those skilled in the art that the compounds according to the present invention embody highly desirable pharmacological properties which could not have been predicted from the prior art knowledge, namely high utilizable spasmolytic activity coupled with extremely low intensity of the side efiects.

The new quaternary compounds may be administered orally, subcutaneously, intramuscularly, intravenously, or topically. The daily oral dose is between 3 mg. and 10 mg. depending on the route of administration. The preferred single dose for adults is 10 mg. and the maximum single dose 20 mg. when administered orally, and 3 mg. to 5 mg, when administered parcnterally.

The new compounds according to the present invention are employed in therapy with great advantage in the treatment of stomach and duodenal ulcers, spasms of the stomach and intestine, of the biliary duct and urinary tract and of spasms of the uterus.

For oral administration the compounds are preferably employed in the form of tablets, pills, dragees, powders, capsules, solutions, emulsions, suspensions, dispersions, or in any other suitable form. They are preferably not used as such but are diluted with suitable diluting agents, thus allowing better and more economical use to be made thereof.

While we have illustrated certain specific embodiments of the present invention, those skilled in the art will readily recognize that our invention is not limited to the illustrative embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. A quaternary compound of the formula wherein V V 7 R and R are each selected from the group consisting of methyl, ethyl and isopropyl, R is alkyl of 6 to 11 carbon atoms, inclusive, and X is a non-toxic, pharmacologically acceptable anion.

2. Benzilic acid ester of I-(dimethyl-n-oCtyLammO- nium bromide)-ethanol-2.

3. Benzil'ic acid ester of 1-(dimethyl-n-heptyl-ammonium bromide)-ethan0l-2.

4. Benzilic acid ester of 1-(dimethyl-n-nonyl-ammonium bromide) ethanol-2.

References Cited by the Examiner UNITED STATES PATENTS OTHER REFERENCES Ford-Moore et al., J. Chem. Soc. (London), volume 0 of 1947, pages 55-60.

Wagner-Jauregg, Ber. Deut. Chem., volume 72, pages 1551-1561 (1939).

References Cited by the Applicant E. B. Sigg, Pharmacology of (2-Benziloxyethyl) Dimethyl (N-OctyD-Arnmoninm Bromide, a New Spasmolytic Agent, Toxicology and Applied Pharmacology, vol. 5, pp. 225-234 (1963).

A. Slanger, Preliminary Clinical Trial of a New Spasmolytic (AD-205) in Gastrointestinal Disorders, Journal of New Drugs, vol. '2, pp. 84400 (1962).

LORRAINE A. WEINBERGER, Primary Examiner.

LEON ZITVER, Examiner. 

1. A QUATERNARY COMPOUND OF THE FORMULA 